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Review

Introduction

Osteoarthritis (OA) is a leading cause of disability in the United States. It is the
most common form of arthritis and afflicts 13.9% of U.S. adults aged 25 and older
and 33.6% (12.4 million) of those over 65—an estimated 26.9 million individuals in
the United States in 2005 [1]. Although knee OA is typically diagnosed from radiograph images showing narrowing
of the joint space and osteophytes, all the components of the knee joint are involved
[2,3]. Consequently, OA is a progressive disease involving extensive inflammation and damage
to not only the joint cartilage and synovium, but also the joint capsule and the bone,
muscle, ligaments and tendons surrounding the joint, with alterations in peripheral
innervation and central pain processing [4] (Figure 1A,B). The result is irreversible structural change and consequent joint stiffness,
pain, and functional impairment [1-4] (Figure 1C).

Although our understanding of the underlying causes of OA is increasing, we are only
beginning to appreciate differences in the disease that exist with respect to sex
or gender. Studies sponsored by the Centers for Disease Control and Prevention and
the National Institutes of Health have identified differences in the incidence and
severity of OA between men and women as well as between racial and ethnic groups [3,5]. The burden of OA is greater in women (Figure 2), who disproportionately develop knee and hand, but not hip OA [5]. The greater number of women in the aging U.S. population is of clinical concern
due to the more severe knee OA experienced by women and its impact on quality of life
and independence. Moreover, early onset OA is becoming more common, particularly among
women who lead physically active lifestyles, such as athletes and workers in occupations
that involve exposure to traumatic injury or mechanical stress. Injuries to the anterior
cruciate ligament are of particular concern in young women (16–20 years) as approximately
50% of them will develop knee OA within 10–15 years [6,7]. As described in greater detail in the three accompanying papers, these observations
underscore the need for research targeted at understanding how sex differences contribute
to the development and progression of OA, and influence prevention and treatment strategies.

Figure 2.Prevalence of arthritis by age group for US men (blue) and women (pink) in 2003–2005
(top panel) and current and projected prevalence of arthritis for US men and women
(bottom panel). The graphs are based on data from the Centers for Disease Control website.

Sex differences and models for studying knee OA

Degenerative arthritis has been studied extensively in mice and other laboratory animals
such as rats, guinea pigs, rabbits, dogs, and more recently, rhesus monkeys [8]. Such studies have been described as indicative of the human clinical condition because
they develop similar histological and morphological abnormalities [8-10] as well as hormonal adaptations and polygenic inheritance in the case of genetic
models [11]. Unfortunately, most studies on the mechanisms underlying OA have not considered
sex differences, whether the studies used in vitro cell culture or animal models.

That sex differences exist in OA was recognized as far back as 1956 [12]. Nonetheless, even with the many animal models that have been developed and studied
since that time, few studies have addressed the issue of sex differences. An extensive
review of animal models published in 1994 [13] made no mention of sex differences. In 1996, Carlson et al. observed that the prevalence
and severity of OA was similar in a limited population of male and female cynomolgus
monkeys, whereas knee OA in humans occurs more commonly in females [14]. As recently as 2001 [15], a review of the literature identified the studies had been conducted using sex-matched
animals, but these were limited in number and to a small group of laboratories: Silberberg
(8 studies, 1941–1963), Walton (6 studies, 1975–1979) and Sokoloff (5 studies, 1956–1962).

The information provided in Table 1, which summarizes all animal studies of osteoarthritis published between 2002 and
2012, underscores the need for well-designed studies addressing sex differences. Out
of a total of 1043 studies, only 32 identified the sex of the animals and only one
of these made a comparison of the results between the sexes. Clearly, investigators
typically do not consider the potential for sex differences in osteoarthritis. Moreover,
the Pubmed database listed 2,968 clinical studies of knee OA in the past 10 years
with 2,189 (73.7%) specifying the sex of the clinical population. Within this population,
only a small percentage identifies "sex" (198 or 9.0%) or "gender" (142 or 6.5%) as
a key parameter of the study (Table 2). These statistics indicate that although sex differences are routinely reported
in clinical studies, they are not necessarily the principal factor on which the studies
are based.

Cell culture studies are similarly limited with respect to the sex of the cell source.
For those studies that use primary cells, whether from animals or humans, most do
not directly compare the same set of experimental parameters for both sexes. Moreover,
there is often a lack of a statistical design that provides sufficient power to adjust
for inter-human variability. When cell lines are used, the sex of the cell is generally
not provided. Thus, statements are made concerning underlying mechanisms that may
not be accurate for the broader population of subjects.

The knee as an organ

Diagnosis of knee OA is based on evidence of joint pain or reduced space between articulating
bone surfaces due to thinning of the opposing articular cartilages. However, multiple
tissues that comprise the knee joint appear to be compromised by the disease, including
subchondral bone, articular cartilage, meniscus, anterior cruciate ligament, synovium
and synovial fluid, and the innervation of these tissues. A change in any of these
tissues can influence the distribution of load across the joint, with corresponding
adaptations in the other tissues and ultimately the cartilages [2]. Such pathophysiologic changes may exacerbate age-related physiologic changes in
joint function attributable to genetic characteristics, age, sex, and health status,
leading to greater cartilage damage. Thus, to better understand how knee OA is differentially
expressed in males and females, it is critical to view the knee as an organ, rather
than focusing only on the articular cartilage [2,3]. Moreover, the development of OA can involve multiple mechanisms, including mechanical
loading, fluctuations in hormonal levels, and modulation of nervous system pathways.

Biomechanics and etiology of knee OA

Experimental and computational data suggest that contact stress in joint cartilage
is a significant predictor of the risk for developing knee OA. Limb alignment, a major
determinant of mechanical stresses within the knee, can predict the development of
radiographic signs of knee OA, but these data do not indicate how limb alignment could
contribute to sex differences. Similarly, little is known about how sex-related changes
in muscle function might contribute to the worsening of knee OA. Significant gaps
in knowledge remain as to how changes in musculoskeletal traits, such as obesity,
disturb the normal mechanical environment of the knee joint and contribute to sex
differences in the initiation and progression of knee OA [16].

Hormonal modulation of the knee

Knee tissues are modulated by sex hormones during tissue development and throughout
the life cycle in both males and females. Whereas menopause in women is associated
with an increase in OA severity, systemic estrogen alone cannot explain the observed
sex differences [17]. Recent data, for example, show that sex-specific variations in the responses of
chondrocytes to sex steroids are due to differences in receptor number as well as
mechanisms of hormone action [18]. Moreover, the reduction in systemic estrogens is accompanied by changes in the relative
levels of other steroid hormones, but how this impacts knee physiology is not known.

Neurologic contributions to knee OA

In addition to a greater prevalence of knee OA, women also often report greater pain
and more substantial reductions in function and quality of life than men [19]. OA pain can be related to the innervation of the knee joint, but the pain does not
always match the degree of injury and can continue even after total joint replacement.
The mechanisms underlying these differences in pain between men and women with knee
OA are unknown [20]. By improving our understanding of the mechanisms responsible for sex differences
in the perception of pain in OA, more effective, and possibly sex-specific, treatment
strategies will emerge.

Conclusion

Epidemiologic studies have established that there are sex differences in the incidence
and severity of knee OA. Therapeutic approaches to the treatment of OA, particularly
regenerative medicine strategies, have not yet taken these sex differences into consideration
[21,22]. Effective interventions, however, will require a better understanding of the mechanisms
involved in the disease and its differential expression in men and women. Although
little is known about the mechanisms that underlie disparities between men and women
in disease incidence and severity, it is likely that mechanical, hormonal, and neural
events in the joint are involved. The papers that follow in this series review the
literature related to sex differences and OA and identify gaps in our understanding
with the goal of motivating research on this important problem.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

This paper was written by the authors to provide an overview of the gaps of knowledge
that exist in the study of sex differences related to osteoarthritis. BDB wrote the
initial draft, which was then edited by the other authors. All authors read and approved
the final manuscript.